In general, pharmaceuticals and the like are freeze-dried by using a freeze-drying device, which is automatically controlled by a control device, introducing a large number of trays, vials, or other containers filled with a to-be-dried material into a drying chamber, and drying the to-be-dried material in each container to a predetermined moisture content. In the above-mentioned freeze-drying process for the to-be-dried material, which is performed by the freeze-drying device, it is important for proper monitoring and optimization of the drying process that an average sublimation interface temperature of the whole to-be-dried material filled into a large number of containers be accurately measured. A conventionally known method of measuring the sublimation interface temperature of the to-be-dried material during a primary drying period of the freeze-drying process inserts a thermocouple or other temperature sensor into at least one of the large number of containers introduced into the drying chamber and directly measures the temperature of the to-be-dried material filled into the container. The drying process is monitored by continuously measuring, from the start of freezing, the temperature of a shelf stage (shelf temperature) in the drying chamber in which containers filled with the to-be-dried material are mounted, the degree of vacuum in the drying chamber, and the sublimation interface temperature of the to-be-dried material (product temperature).
However, when the product temperature is measured by the temperature sensor, the following problems occur.
(1) The product temperature measured by the temperature sensor is the temperature of a portion of a to-be-dried material into which a temperature sensing element of the temperature sensor is inserted. This does not represent the product temperature of the whole to-be-dried material introduced into the drying chamber.(2) As the temperature sensor is not always disposed at the same location, the degree of reproducibility is low.(3) The degree of supercooling of the to-be-dried material in the container into which the temperature sensor is inserted is decreased by nucleation temperature and ice crystal growth. Therefore, an average ice crystal size increases to reduce the water vapor resistance of a dried layer, thereby increasing the sublimation rate. Further, the to-be-dried material is affected by radiant heat input from a drying chamber wall depending on the position of a shelf on which the container into which the temperature sensor is inserted is mounted. Therefore, the to-be-dried material does not represent the whole to-be-dried material in the containers because it differs in a drying rate, for instance, from a to-be-dried material in a container placed at a location apart from the drying chamber wall.(4) As described above, the to-be-dried material into which the temperature sensor is inserted exhibits a high drying rate. Therefore, if a point of time at which there is no difference between the product temperature of the to-be-dried material into which the temperature sensor is inserted and the shelf temperature is regarded as the end point of primary drying, it is possible that ice may be left on the to-be-dried material in a container placed at the center of the shelf. Consequently, the to-be-dried material may be introduced into a secondary drying process before being completely sublimated, and collapse (become defective and unrecoverable without being dried to required dryness).(5) In consideration of work efficiency, the temperature sensor has to be manually set in a container. Meanwhile, as regards the sterile formulation of a pharmaceutical, it is stipulated that a partially stoppered container must be handled in an important process zone. However, according to a regulatory authority, a problem occurs if a person installs the temperature sensor by leaning over a laminar flow of grade A and bending over an array of containers. Consequently, as regards at least the sterile formulation of a pharmaceutical, it is difficult to let a person enter a grade A area in order to set the temperature sensor in its place. At present, regulatory guidelines in various countries also stipulate strict regulations concerning a process of loading a partially stoppered container filled with a medical solution to the shelf of the freeze-drying device. Such regulations point out a risk of causing the partially stoppered container to be contaminated when it is manually transported or transferred to the shelf. Under the above circumstances, a latest technology is adopted to automate a process of transferring the partially stoppered container from a filling machine to the shelf of the freeze-drying device. However, an automatic loading device does not measure the product temperature because it cannot make product temperature measurements on individual containers. In an actual sterile formulation of a pharmaceutical, therefore, the product temperature measurements are made on the individual containers during the validation of three lots at a production start-up stage, and when a required product evaluation is obtained from the results of the measurements, subsequent production is conducted merely by managing parameters indicative of the shelf temperature and the degree of vacuum.
Under the above circumstances, a method called the MTM (Manometric Temperature Measurement) method is conventionally proposed. The MTM method performs calculations on measured values of the other parameters to determine the sublimation interface temperature of the to-be-dried material instead of directly measuring the sublimation interface temperature. This method is applied to a freeze-drying device W that includes a drying chamber DC and a cold trap CT as shown in FIG. 1. The drying chamber DC is a chamber into which the to-be-dried material is introduced. The cold trap CT condenses and traps water vapor generated from the to-be-dried material introduced into the drying chamber DC. The drying chamber DC communicates with the cold trap CT through a main pipe a having a main valve MV. During the primary drying period of the to-be-dried material, the main valve MV is closed for a period of more than 10 seconds at fixed time intervals to measure changes in the degree of vacuum in the drying chamber DC with an absolute vacuum gauge at a measurement rate of 1 second or lower. The sublimation interface temperature Ts and the dried layer water vapor resistance Rp are then calculated from the measured changes in the degree of vacuum (refer to Nonpatent Literature 1).
As described above, when a vacuum freeze-drying device is activated to start a primary drying process with the to-be-dried material introduced into the drying chamber DC, the MTM method periodically closes the main valve MV between the drying chamber DC and the cold trap CT at fixed time intervals to isolate the drying chamber DC from the cold trap CT. This temporarily inhibits the cold trap CT from condensing and trapping the water vapor generated from the to-be-dried material in the drying chamber DC. When the drying chamber DC is isolated from the cold trap CT, the water vapor sublimated from the to-be-dried material rapidly raises the pressure in the drying chamber DC to a sublimation interface pressure of the to-be-dried material. Subsequently, the vacuum pressure in the drying chamber increases with an increase in the product temperature. The average sublimation interface temperature of the to-be-dried material is then calculated from the changes in the degree of vacuum in the drying chamber. The degree of vacuum in the drying chamber needs to be measured with a vacuum gauge b that is capable of measuring an absolute pressure. It is also necessary to collect data at a fast recording speed, that is, within a period of 1 second or shorter.
However, the MTM method has the following two problems.
(1) When the main valve MV is fully closed, the pressure in the drying chamber DC rises to the sublimation interface pressure or higher, thereby raising the sublimation interface temperature to a collapse temperature of the to-be-dried material or higher. Therefore, a dried product may collapse, resulting in unsuccessful freeze drying.(2) When the MTM method is exercised, the main valve MV needs to be instantaneously opened and closed. However, when a common production machine is used, it takes several minutes to open and close the main valve MV. This complicates the calculation of the sublimation interface temperature. Further, when the main valve MV is opened and closed with a delay, the degree of vacuum in the drying chamber DC further decreases. This also makes the to-be-dried material easily collapsible.
FIG. 2 shows an example of a monitoring result of a freeze-drying process performed by the MTM method. The freeze-drying process was performed by using a 5% water solution of sucrose as the to-be-dried material. The sublimation interface temperature Ts of the to-be-dried material mounted on the shelf of the drying chamber DC was calculated by the MTM method during the primary drying period. Further, for verification purposes, a temperature sensor (thermocouple) was inserted into the to-be-dried material in a vial placed at an end of the shelf and into the to-be-dried material in a vial placed at the center of the shelf in order to measure not only the product temperature Tm (side) at the end of the shelf and the product temperature Tm (center) at the center of the shelf, but also the shelf temperature (Th). As is obvious from FIG. 2, the sublimation interface temperature Ts of the to-be-dried material that was calculated by the MTM method is substantially equal to the product temperature Tm (side) at the end of the shelf and the product temperature Tm (center) at the center of the shelf, which were measured by the temperature sensor. It indicates that the sublimation interface temperature Ts of the to-be-dried material can be accurately measured by using the MTM method.